Automated detection of uveitis using optical coherence tomography

ABSTRACT

Systems and methods for automatically detecting, classifying and quantifying clumps indicative of inflammation in the eye using optical coherence tomography images are described. Clump detection relies on both intensity and geometric thresholding. Applications of the invention include improved diagnosis, classification and monitoring of inflammatory disease.

PRIORITY

This application is a Continuation of U.S. patent application Ser. No.13/449,227, filed Apr. 17, 2012, which claims priority to U.S.Provisional Application Ser. No. 61/478,741, filed Apr. 25, 2011, herebyincorporated by reference.

TECHNICAL FIELD

The invention described herein relates to improved diagnosis in thefield of ophthalmology. In particular the invention describes anautomated method to detect, classify and quantify clumps indicative ofinflammation in the eye using optical coherence tomography images.

BACKGROUND

Uveitis is swelling and inflammation of the uvea, the middle layer ofthe eye. The uvea consists collectively of the iris, the choroid, andthe ciliary body. Uveitis can exist in the front of the eye (anterioruveitis or iritis), the middle region of the eye (intermediate uveitis),the back of the eye (posterior uveitis), or throughout the eye(panuveitis or diffuse uveitis). The most common form of uveitis isanterior uveitis, which involves inflammation in the front part of theeye, usually the iris. Anterior uveitis can be divided into acute andchronic types based on the duration of the inflammation. A furtherclassification is granulomatous and non-granulomatous. Granulomatousuveitis presents with large, greasy precipitates on the cornealendothelium with large clumps of inflammatory cells present in theanterior chamber because of exuberant macrophage activity.Nongranulomatous uveitis presents with fine cornea endothelialprecipitates and anterior chamber activity (clumps). Uveitis can begraded based on the number of cells present in the aqueous according tothe Standardization of Uveitis Nomenclature (SUN). Slit-lamp examinationis the standard method for assessment of the inflammatory reaction incase of uveitis. However clinical assessment is subjective and oftendifficult in eyes with corneal opacification.

Optical Coherence Tomography is a non-invasive, in-vivo imagingtechnique based on the back-scatter or reflectivity of light in amedium. In ophthalmic examinations, the beam of light produced by theOCT device scans the eye through the pupil and the image formationprocess records the back-scattering profile of the light at eachlocation. The amount of scatter is indicative of the reflectivity of thetissue encountered, and a grayscale cross-sectional image is formed asthe light beam sweeps across the field of view (FOV). OCT imaging hasdramatically advanced ophthalmic diagnostic capabilities and led also tobetter understanding of ocular anatomy. It is an established basis ofroutine ophthalmic practice. Several implementations of OCT have beendeveloped including time domain (TD-OCT) and frequency domain (FD-OCT)(spectral domain (SD-OCT) and swept-source (SS-OCT)).

The clumps of inflammatory cells present in the anterior chamber ofpatients with uveitis appear as bright or hyperreflective spots in OCTimages. US 2009/0244485 describes a method for determining or assessingrisk of uveitis based on the intensity levels of the image signal ascompared to a database of normal and abnormal values. Agarwal et alcompared manual and automated counting of the hyperreflective spots inOCT images of the hyperreflective spots in anterior chamber OCT (Agarwalet al “High Speed Optical Coherence Tomography for Imaging AnteriorChamber Inflammatory Reaction in Uveitis: Clinical Correlation andGrading” Am J Ophthalmology 147(3): 413-416 2009). The images werepost-processed using Matlab.

The methods described above are based on a numerical count of the numberof cell clumps. The present invention introduces the concept of usingOCT for providing an automated measurement of the shape and volume ofthese clumps. A further inventive aspect is the classification of theclumps into different types such as pigment clumps and cell clumps basedon the reflectivity, size, shape and other parameters. Differentiatingcells and cell clumps from pigment clumps would allow the level of cellspresent (an indication of disease status) to be estimated independent ofsurgical events that might release pigment from the iris into theanterior chamber.

SUMMARY

The present invention describes a method for automatically segmenting,classifying and quantifying clumps indicative of inflammation in the eyeusing OCT images. The methods described herein can provide aquantitative measure of the number and density of hyper-reflectiveclumps in the anterior chamber. It will also be possible to classifydifferent types of hyper-reflective spots (i.e. pigment clumps vs. cellclumps) and quantify their density separately. By automating the processof clump detection using OCT imaging and image processing, the presentinvention removes the subjectivity of manual slit-lamp evaluationtechnique for assessing the inflammatory reaction. While the inventiondescribed herein applies to uveitis, it could be applied to anyinflammation of the eye involving the presence of cellular clumps in theanterior chamber of the eye.

The methods described herein can be applied to the following situations:

1. Analysis of anterior segment OCT images for Uveitis diagnosis.

2. Analysis of posterior segment OCT images for diseases that causehyper-reflective spots to occur in the vitreous.

3. Analysis of anterior segment images to obtain quantitativemeasurements—hyper-reflective spot count/B-Scan, density etc.

4. Provide a way to visualize hyper-reflective spot detection to theuser.

5. Monitoring of treatment efficacy, progression of disease.

The patent or application file contains at least one drawing executed incolor. Copies of this patent or patent application publication withcolor drawing(s) will be provided by the Office upon request and paymentof the necessary fee.

BRIEF DESCRIPTION OF FIGURES

FIG. 1 is a generalized OCT instrument that can be used to provide datafor the present invention.

FIG. 2 is a flow chart illustrating the steps of the invention.

FIG. 3 shows cell clumps in (a) normal and (b) inverted grayscaleimages.

FIG. 4( a) shows an inverted gray scale image of clumps against a brightbackground. FIG. 4( b) shows the binary mask created as a step in theinventive method. FIG. 4 (c) shows the result of the segmentation aftermorphological processing and FIG. 4( d) shows a visualization of thesegmented clumps.

FIG. 5 shows an original image (a) and a visualization of thesegmentation (b) from the anterior chamber of a healthy patient.

FIG. 6 shows an original image (a) and a visualization of thesegmentation (b) from the anterior chamber of a patient with uveitis.

DETAILED DESCRIPTION

An optical coherence tomography scanner, illustrated in FIG. 1 typicallyincludes a light source, 101. This source can be either a broadbandlight source with short temporal coherence length or a swept lasersource. (See for example, Wojtkowski, et al., “Three-dimensional retinalimaging with high-speed ultrahigh—resolution optical coherencetomography,” Ophthalmology 112(10):1734 2005 or Lee et al. “In vivooptical frequency domain imaging of human retina and choroid,” OpticsExpress 14(10):4403 2006)

Light from source 101 is routed, typically by optical fiber 105, toilluminate the sample 110, a typical sample being tissues in the humaneye. The light is scanned, typically with a scanner 107 between theoutput of the fiber and the sample, so that the beam of light (dashedline 108) is scanned laterally (in x and y) over the area or volume tobe imaged. Light scattered from the sample is collected, typically intothe same fiber 105 used to route the light for sample illumination.Reference light derived from the same source 101 travels a separatepath, in this case involving fiber 103 and retro-reflector 104. Thoseskilled in the art recognize that a transmissive reference path can alsobe used. Collected sample light is combined with reference light,typically in a fiber coupler 102, to form light interference in adetector 120. The output from the detector is supplied to a processor121. The results can be stored in the processor or displayed on display122. The Fourier transform of the interference light reveals the profileof scattering intensities at different path lengths, and thereforescattering as a function of depth (z-direction) in the sample (see forexample Leitgeb et al, “Ultrahigh resolution Fourier domain opticalcoherence tomography,” Optics Express 12(10):2156 2004). The profile ofscattering as a function of depth is called an axial scan (A-scan). Aset of A-scans measured at neighboring locations in the sample producesa cross-sectional image (tomogram or B-scan) of the sample. A collectionof B-scans makes up a data cube or cube scan.

The different elements of the present invention are shown in FIG. 2. Themethod starts with OCT image acquisition 201. The method described herecould be applied to different types of

OCT scans. For example, it could be applied to high definition OCTB-Scans that have been speckle reduced (1024×1024 B-Scans averaged 4times or 20 times) or individual B-Scans from cube scans . The onlyrequirement is that the axial and lateral resolution of the OCT imageshould be sufficient to visualize the cell clumps. In order to get 3Dinformation, the B-Scans should also be spaced close enough to capturethe extent of the clumps. A specific scan pattern could be 21 B-Scans,each with 1024×1024 points over a 6 mm scan region along the xdimension, 2-mm scan depth. The B-Scans could be separated by 10 micronsto give a total sampling volume of 6 mm×2 mm×0.2 mm. Higher densityscans could be imagined, especially with the advent of very high speedswept-source OCT systems.

Once OCT image data is obtained, the second step in the process is asmoothing of the image data to reduce noise 202. This might beaccomplished using linear filters such as Gaussian smoothing filters,box filters or non-linear filters such as median filters, anisotropicdiffusion filters or bilateral filters. Non-linear filters are bettersuited for smoothing because of their edge-preserving characteristicswhile suppressing noise. An optional step in the processing might be tosub-sample the image to obtain a lower resolution image. This step mightbe done if it is desirable to speed up the processing time and if theoriginal image resolution was sufficiently high so that down-samplingdoes not affect the visualization of the structures of interest.

We are interested in segmenting the cell-clumps that appear in theanterior chamber or the posterior chamber of the eye. Hence it isdesirable to detect and exclude the tissue regions in the image fromfurther processing 203. The tissue region to be excluded corresponds tothe cornea in the case of an anterior segment scan and the retina in thecase of a posterior segment scan. For example, in anterior segmentscans, once the cornea is detected, the clump detection can be carriedout on regions below the posterior cornea. In the same way for aposterior segment scan, the clump—detection would be carried out onregions above the retina. Thus this step is mainly aimed at extractingthe region of interest within the image where the clump detection wouldbe executed. Various methods have been described in the literaturepreviously for the segmentation of the above structures and thoseskilled in the art can easily adapt any existing methods for thispurpose.

Once the region of interest is determined, the next step in the processis to identify the clump locations. One possible implementation of thisis described here and is referred to as intensity based blob detection204. Additional implementations can be imagined by one skilled in theart. The clumps typically appear as bright spots against the relativelylow intensity vitreous humor (the clear gel that fills the space betweenthe lens and the retina of the eyeball) or the aqueous humor (thickwatery substance filling the space between the lens and the cornea).FIG. 3( a) shows the zoomed in view of a cell clump 301 obtained fromthe anterior chamber of the eye. FIG. 3( b) shows how the clump 301might be visualized better using an inverted gray-scale image.

These bright intensity blobs can be segmented 204 using an adaptivethresholding strategy that adjusts itself to the local intensities inthe image. Consider a pixel at location (x,y,z). The intensities of theimage inside a box of size (W1×W2×W3) centered at location (x,y,z) areextracted from the image and the mean (or the median) of theseintensities are calculated. The dimensions of the box—W1, W2 & W3 can bechosen based on the pixel resolutions and on the expected size of theclumps so as to enclose the full clump in a box. Now the central pixelat (x,y,z) can be marked as belonging to a clump if the intensity at(x,y,z) is significantly more than the mean intensity within the box.This strategy allows the thresholding to be much more robust to localintensity changes across the image. The above process is repeated ateach of the pixel locations in the region of interest identifiedearlier. The result of this step is a binary mask with “ones” indicatingpossible clump locations and “zeros” indicating background regions. FIG.4( a) shows a sample image that can be processed using the presentinvention. The image is shown in inverted gray scale to enhancevisualization of clumps 401 in the aqueous humor 402 (light backgroundarea). The top layer shown in the figure is the posterior cornea 403.FIG. 4( b) shows the associated binary detection mask for a single slicebased on the blob segmentation. As can be seen, this binary mask isnoisy and needs to be further processed to segment only the clumps. Thisis done using morphological operations as will be described next.

We can use the observation that the actual clumps of interest are withina particular size or shape range to place geometric constraints on theanalysis of the clumps 205. The other information that is used is thatthe cell clumps appear as elongated blobs along the horizontal axis.Hence we morphologically filter the initial segmentation mask and retainonly connected components in the mask that have areas in a particularrange and are oriented along the x-axis to produce a final segmentation206. FIG. 4( c) shows the result of this morphological operation tocreate the final segmentation mask on a particular B-scan.

Once the final segmentation is complete, it will be possible tovisualize 208 or quantify 207 the clumps in various ways to extractadditional information. FIG. 4( d) shows one such visualization in whichall detected clumps are circled. Classification of the clumps intocategories like cell clumps and pigment clumps can be done by furtheranalysis of the intensity characteristics of the clumps andmorphological characteristics. These classifications might add furtherdiagnostic value to the clinician about the condition of the subjectbeing imaged and eliminate the problem of counting pigment clumps ascell clumps in grading uveitis. In addition, density measurements couldbe obtained for each type of clump separately.

From the number of clumps found from each OCT B-Scan, a densitymeasurement could be made based on the volume being imaged. Inparticular, the segmentations could be used to derive quantitativemeasurements such as number of clumps/B-Scan, size of each clump,density of the clumps/unit area, and density of the clumps/unit volumeamong others.

FIGS. 5 and 6 show sample results from representative B-Scans for twodifferent subjects. FIG. 5( a) shows the original OCT image of theanterior chamber of a patient while FIG. 5( b) shows the segmented imagehighlighting the cell clump 501 evident in the image. FIG. 6( a) and (b)show the same types of images for a patient who has undergone surgeryfor uveitis and as can be seen the density of cell clumps is much largerin that subject indicating inflammatory reaction.

A further aspect of this invention is proposing an easy way toautomatically validate or invalidate the generated results based oninput from the clinician. A particular embodiment of this would be todisplay the detected clumps to a user as shown in FIGS. 5( b) and 6(b)and the user only has to click on or otherwise designate what theybelieve are false detections, and the system would remove that clumpfrom further calculations. This could be done in the opposite way, wherethe clinician clicks on the detected clumps they believe are correct,but this would be more time-consuming as it is imagined that the falsedetections would be fewer than the correct detections. In addition, thevarious qualitative and quantitative characterizations of cell clumpscan be used to grade the disease, track the disease progression overtime, and monitor treatment efficacy. Data from two separateexaminations at different times can be compared to determine the rate ofdisease progression and make predictions on future progression.

Although various embodiments that incorporate the teachings of thepresent invention have been shown and described in detail herein, thoseskilled in the art can readily devise many other varied embodiments thatstill incorporate these teachings.

The following references are hereby incorporated by reference:

US Patent Publication No. 2009/0244485 Walsh et al. “Optical CoherenceTomography Device, Method, and System”

Agarwal et al, “High-Speed Optical Coherence Tomography for ImagingAnterior Chamber Inflammatory Reaction in Uveitis: Clinical Correlationand Grading” American Journal of Ophthalmology 147(3): 413-416 2009.

Agarwal et al “Using OCT to assess anterior chamber inflammation”Ophthalmology Times Europe 4(2) March 2008.

Lowder et al. “Anterior Chamber Cell Grading with High-Speed OpticalCoherence Tomography” IOVS 2004; 45 E-abstract 3372.

Wojtkowski, et al., “Three-dimensional retinal imaging with high-speedultrahigh—resolution optical coherence tomography,” Ophthalmology112(10):1734 2005.

Lee et al. “In vivo optical frequency domain imaging of human retina andchoroid,” Optics Express 14(10):4403 2006.

Leitgeb et al, “Ultrahigh resolution Fourier domain optical coherencetomography,” Optics Express 12(10):2156 2004.

Kim et al. “The role of imaging in the diagnosis and management ofuveitis” Expert Rev. Ophthalmol. 5(5) 699-713 2010.

1. (canceled)
 2. A method for automatically identifying inflammatoryclumps within the eye from image data obtained with an optical coherencetomography (OCT) system, the method comprising: identifying the regionof the tissue from within the image data that will be searched forclumps; identifying locations in the region that have a brightness abovea threshold and have geometric properties that fall within a particularrange associated with clumps; and storing, displaying or quantifying theidentified clumps.
 3. A method as recited in claim 2 further includingthe step of calculating the brightness threshold based on the intensityof the image data in the region.
 4. A method as recited in claim 2further including the step of dividing the identified region into aplurality of sub-regions and calculating separate brightness thresholdsfor each sub-region based on the intensity of the image data in eachsub-region.
 5. A method as recited in claim 4 wherein the brightnessthreshold is derived based on a calculation of the mean intensity of thesub-region.
 6. A method as recited in claim 4 wherein the brightnessthreshold is derived based on a calculation of the median intensity ofthe sub-region.
 7. A method as recited in claim 2, wherein prior toidentifying the region of the tissue from within the image data thatwill be searched for clumps, the image data is smoothed.
 8. A method asrecited in claim 2, wherein an image is generated and displayed thatpermits visualization of the size and location of the identified clumps.9. A method as recited in claim 8, wherein the image is displayed to aclinician on a user interface and further comprising validating theautomatically detected clumps based on input from the clinician.
 10. Amethod as recited in claim 1, wherein one or more of a) the number ofidentified clumps, b) the volume of identified clumps, and c) thedensity of the clumps in a region are calculated and then displayed orstored.
 11. A method as recited in claim 10, wherein the number ofclumps is calculated and the number is used to automatically determine auveitis grade based on Standardization of Uveitis Nomenclature.
 12. Amethod as recited in claim 2, further comprising analyzing one or bothof the intensity characteristics of the clumps and morphologicalcharacteristics to categorize the clumps as cell clumps or pigmentclumps.
 13. A method as recited in claim 12, further comprisingseparately quantifying properties of each type of clump.
 14. A method asrecited in claim 2, further comprising classifying the subject intodisease categories based on the quantitative information.
 15. A methodas recited in claim 2, further comprising 3D volume rendering of theclumps.
 16. A method as recited in claim 2, further comprising making anassessment on the infection status of the eye of the patient based onthe detected clumps.
 17. A method as recited in claim 2, furthercomprising comparing the information on the identified clumps tomeasurements from a prior examination and providing the user with changeanalysis of the measurements to evaluate progression.
 18. An opticalcoherence tomography (OCT) system for identifying inflammatory clumpswithin the eye of a patient, said OCT system comprising: a light sourcearranged to generate a beam of radiation a beam divider for separatingthe beam along a sample arm and a reference arm; optics for scanning thebeam in the sample arm over a set of transverse locations on the eye; adetector for measuring radiation returning from both the sample arm andthe reference arm, the detector generating output signals in responsethereto; and a processor for converting the output signals into imagedata, said processor identifying the region of the tissue from withinthe image data that will be searched for clumps and then identifyinglocations in the region that have a brightness above a threshold andhave geometric properties that fall within a particular range associatedwith clumps.
 19. An OCT system as recited in claim 18 wherein saidprocessor calculates the brightness threshold based on the intensity ofthe image data in the region.
 20. An OCT system as recited in claim 18wherein said processor divides the identified region into a plurality ofsub-regions and calculates separate brightness thresholds for eachsub-region based on the intensity of the image data in each sub-region.21. An OCT system as recited in claim 20 wherein the brightnessthreshold is derived based on a calculation of the mean intensity of thesub-region.
 22. An OCT system as recited in claim 20 wherein thebrightness threshold is derived based on a calculation of the medianintensity of the region.
 23. An OCT system as recited in claim 18,further including a display for displaying an image of the eye includingthe size and location of the identified clumps.
 24. An OCT system asrecited in claim 23, wherein the image is displayed to a clinician on auser interface that permits the clinician to enter information tovalidate the identified clumps.
 25. An OCT system as recited in claim23, wherein the processor determines one or more of a) the number ofidentified clumps, b) the volume of the identified clumps, and c) thedensity of the clumps in a region and the result is displayed on thedisplay or stored in a database for future use.
 26. An OCT system asrecited in claim 25, wherein the processor quantifies the volume of theclumps and the volume is displayed on the display.
 27. An OCT system asrecited in claim 18, wherein the processor analyzes one or both of theintensity characteristics of the clumps and morphologicalcharacteristics to categorize the clumps as cell clumps or pigmentclumps.
 28. An OCT system as recited in claim 27, wherein the processorseparately quantifies the properties of each type of clump.
 29. An OCTsystem as recited in claim 18, wherein the processor compares theidentified locations to clumps identified in a previous examination ofthe patient.